Modern vaccine and other immune strategies take for granted that the mechanisms that define the B cell antibody repertoire and underlie B cell primary and memory responses are relatively well understood. However, our recent studies underscore an important gap in this understanding. We have plays a key role in regulating B- 1a autoantibody production. To explore the mechanisms underlying this CTLA4-mediated B-1a regulation, we generated conditional knockout mice (CKO) in which CTLA4 is specifically deleted in B cells but remains normal in T cells. Our preliminary studies show that ablation of CTLA4 in B cells results in a) increased B-1a expansion; b) spontaneous formation of germinal centers (GC) in spleen; and c) a striking increase in hyper-mutated class- switched B cells whose origins (B-1a or other B) remain elusive. As a result, serum IgG and IgE are remarkably elevated in CTLA4 B cell CKO mice. Intriguingly, we also find that T follicular helper cells (CXCR5+PD-1hiBcl6+), a specialized CD4 T effector subset that provides essential help for GC B cells, is spontaneously induced in CTLA4 B cell CKO mice. Consistent with this finding, we further find that like typical GC responses induced by immunizing with foreign antigens, the spontaneous GC responses in CTLA4 B cell CKO depend on CD4 T cells and CD40 signaling. Finally, we find that autoreactive IgG and IgE, e.g., anti-ANA and anti-dsDNA, are generated in CTLA4 B cell CKO mice and that these mutant mice develop autoimmune pathology as animals age. Taken all together, these findings strongly argue that, as in T cells, CTLA4 also acts as a key checkpoint regulator for B-1a function. In studies here, we focus on the cellular and molecular mechanism(s) that mediate CTLA4 regulation of B- 1a activation, thereby controlling B-1a IgM and IgG natural antibody production and their other immune functions. Our findings potentially offer insights into the mechanisms operating in antibody-mediated autoimmune diseases. Beyond autoantibody production, our studies can be expected to elucidate previously unrecognized roles that B- 1a cells play in maintaining immune homeostasis and self-tolerance. Of practical interest, studies here may offer insights into the mechanism underlying the pathologic autoimmune responses associated with the otherwise promising ?CTLA4 blockade? immune therapy for advanced human neoplasms.